Lipoprotein-associated phospholipase A2 (Lp-PLA2) is, previously known as platelet-activating factor acetylhydrolase (PAF-AH), a phospholipase A2 enzyme involved in hydrolysis of lipoprotein lipids or phospholipids. Lp-PLA2 travels with low-density lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules during the oxidation of LDL. (See Zalewski A, et al., Arterioscler. Thromb. Vasc. Biol., 25, 5, 923-31 (2005)). Lp-PLA2 hydrolyzes the sn-2 ester of the oxidized phosphatidylcholines to give lipid mediators, lyso-phosphatidylcholine (lysoPC) and oxidized nonesterified fatty acids (NEFAs). It has been observed that lysoPC and NEFAs elicit inflammatory responses. (See Zalewski A, et al. (2005)).
Research data has indicated that LysoPC promotes atherosclerotic plaque development, which can ultimately lead to the formation of a necrotic core. (See Wilensky et al., Current Opinion in Lipidology, 20, 415-420 (2009)). Further, the effect of Lp-PLA2 inhibitors on atherosclerotic plaque composition was demonstrated in a diabetic and hypercholesterolemic porcine model of accelerated coronary atherosclerosis. (See Wilensky et al., Nature Medicine, 10, 1015-1016 (2008)). Therefore, it has also been postulated that Lp-PLA2 inhibitors may be used to treat atherosclerosis.
Additionally, studies have shown that the level of Lp-PLA2 is an independent risk factor in coronary artery disease. (See Packard et al, N. Engl. J. Med., 343, 1148-1155 (2000)). Thus, it was believed that Lp-PLA2 inhibitor can be beneficial to treat disease that exhibit vascular dysfunction, for example, diabetes, hypertension, angina pectoris and/or after ischaemia and reperfusion.
It has been reported that high Lp-PLA2 activity is associated with high risk of dementia, including Alzheimer's disease (AD) (See Van Oijen, et al. Annals of Neurology, 59,139(2006)). Higher level of oxidized LDL has also been observed in AD patients (See Kassner et al. Current Alzheimer Research, 5, 358-366 (2008); Dildar, et al., Alzheimer Dis Assoc Disord, 24, April-June (2010); Sinem, et al. Current Alzheimer Research, 7, 463-469 (2010)). Further, research data has shown that neuroinflammation are present in AD patients and multiple cytotoxic inflammatory cytokines are up-regulated in AD patients. (See Colangelo, et al., Journal of Neuroscience Research, 70, 462-473 (2002); Wyss-Coray, Nature Medicine, 12, September (2006)). Research has shown that LysoPC function as a pro-inflammatory factor inducing multiple cytotoxic inflammatory cytokine release (See Shi, et al. Atherosclerosis, 191, 54-62 (2007)). Therefore, it has been believed that the inhibitors of Lp-PLA2 can be used to treat AD by inhibiting activity of Lp-PLA2 and reducing lysoPC production.
In addition, the treatment of an Lp-PLA2 inhibitor on a diabetic and hypercholesterolemia swine model demonstrated that the blood-brain-barrier leakage and the brain amyloid beta protein (Aβ) burden, the pathological hallmarks of Alzheimer's disease, were reduced. (See U.S. Patent Application Publication No. 2008/0279846). This observation suggested that Lp-PLA2 inhibitors have a therapeutic effects on Alzheimer's disease. The restoration of blood-brain-barrier leakage also suggests that Lp-PLA2 inhibitors will be beneficial to vascular dementia treatment.
Further, neuroinflammation, including multiple cytotoxic cytokine release, is a common feature of all neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc. (See Perry, Acta Neuropathol, 120, 277-286 (2010)). As discussed above, Lp-PLA2 inhibitors can reduce inflammation, for example, reducing multiple cytokine release by suppressing lysoPC production. (See Shi, et al. Atherosclerosis 191, 54-62 (2007)). Thus, it has been believed that Lp-PLA2 is a potential therapeutic treatment for neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, etc.
In addition to the inflammatory effect, LysoPC has been implicated in leukocyte activation, induction of apoptosis and mediation of endothelial dysfunction (Wilensky et al, 2009). Therefore, it is believed that Lp-PLA2 inhibitors can be used to treat tissue damage associated with diabetes by reducing the production of lysoPC, which can cause a continuous cycle of vascular inflammation and increased reactive oxygen species (ROS) production. In light of the inflammatory roles of Lp-LA2 and the association between localized inflammatory processes and diabetic retinopathy, it is postulated that Lp-PLA2 can be used to treat diabetic eye disease.
Glaucoma and age-related macular degeneration (AMD) are retina neurodegenerative diseases. Studies suggested that inflammation, including TNF-alpha signaling, may play an important role in the pathogenesis of glaucoma and AMD (See Buschini et al., Progress in Neurobiology, 95, 14-25 (2011); Tezel, Progress in Brain Research, vol. 173, ISSN0079-6123, Chapter 28). Thus, considering Lp-PLA2 inhibitors' function of blocking inflammatory cytokine release (See Shi, et al. Atherosclerosis, 191, 54-62 (2007)), it is believed that Lp-PLA2 inhibitors can provide a potential therapeutic application for both glaucoma and AMD.
In view of the number of pathological responses that are mediated by Lp-PLA2, attempts have been made to prepare compounds that inhibit its activity. Though a number of such compounds have been disclosed in the art, there remains a continuing need for inhibitors of Lp-PLA2 which can be used in the treatment of a variety of conditions.